AZD9291 is a third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor which is developed by the AstraZeneca UK Company. and can be used for activating resistance-mutated EGFR. AZD9291 was granted as a ‘breakthrough therapy drug’ by Food and Drug Administration (FDA) in April 2014, the drug is an oral drug, and is improved for overcoming shortcomings of a first-generation EGFR targeted drug, and therefore, the side effects such as diarrhea and skin rash are fewer than the side effects of the first-generation EGFR targeted drug. According to the annual meeting report of American Society of Clinical Oncology (ASCO) in 2014, the curative effect of AZD9291 for treating T790M mutation people whose diseases were progressed after those people were treated by the first-generation EGFR targeted drug was 66%. The total disease control rate of mutation positive patients treated with AZD9291 was 94%.
The chemical name of AZD9291 is N-{2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indole-3-yl)-2-pyrimidyl]amino]phenyl}-2-propenamide, and a structural formula of AZD9291 is:

International patent WO2013014448 has reported a synthetic method of AZD9291, and preparation steps of the synthetic method comprise coupling on an indole derivative and dichloropyrimidine, substitution on the indole derivative and a phenylamine derivative, condensation on a fluoride parent ring and substituted ethylenediamine, reduction of nitro, amidation, reduction and dehydrogenation and the like to prepare AZD9291 (I).

In addition, in literatures J. Med. Chem, 2013, 56, pp 7025-7048 and 2014, 57, pp 8249-8267, the above synthetic routes are partially improved and optimized, and improvement and optimization are mainly embodied on two aspects: firstly, the N-methylation reaction sequence of indole is improved and optimized, and methylation reaction is carried out after 3-position coupling reaction; and secondly, amidation reaction is improved, allyl acyl chloride is directly used as an acylating agent, a reaction process is simplified, and the reaction yield is increased.

According to analysis on the disclosed preparation method for AZD9291, in the basic thinking, pyrimidine rings are successively connected through 3-position coupling for forming an indole ring, and then through reactions such as substitution, reduction and amidation on the pyrimidine rings successively, functional-group transformation of a side chain is realized, and therefore, a target compound is prepared. These methods have the shortcomings of rare raw materials, more steps, higher cost and the like. Although reactions such as N-methylation and amidation of indole were optimized in literature report, only local reactions are optimized, in the core reaction route, preparation is realized by step-by-step accumulation of functional groups of a starting material, and obviously, the synthesis idea does not conform to the concept about atom economy in the modern green chemistry.
For overcoming existing process defects, a preparation technology which is simple in process, economical and environmentally friendly, and high in quality is developed, and particularly, a process technology capable of adapting to industrial production needs to be sought, and is of great realistic significance on improvement of the economic and social benefits of the drug.